Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence, which leads to the development of hepatocellular carcinoma and autoimmune disease. In chronic HCV patients, cellular immune responses including the production of IL-12 and IFN-g are severely impaired. In addition, HCV-induced immune suppression is associated with increased susceptibility to bacteria and other enteric viral infections. Thus, HCV most likely evolved a strategy to avoid host immune surveillance by encoding gene products, which are capable of dampening host immune responses. To understand the mechanism(s) of immune evasion by HCV and to design strategies for therapeutics and improved immunization, we identified the HCV core protein as an immunomodulatory molecule to inhibit IL- 12 production. In addition, we successfully demonstrated a novel interaction between HCV core and complement receptor (gClqR). Clq is a ligand for gClqR and plays a critical role in innate immunity, as well as, regulation of adaptive immunity. Intriguingly, the binding of extracellular core protein to gClqR on macrophages induced SHP-1 recruitment and SOCS1 mRNA expression. Both SHP-1 and SOCS1 play a role in suppressing intracellular signaling for inflammatory cytokine production. Based on these findings, we hypothesize that the binding of soluble core protein to the gClqR on macrophages leads to SHP-1 and/or SOCSl-dependent suppression of IL-12 production. In this proposal, we will first determine protein(s) recruited to HCV core/gC1qR complex for inhibition of IL- 12 production. Second, we will characterize the role of SHP-1 and SOCS1 in inhibition of IL-12 production by HCV core/gClqR engagement. Third, we will analyze the mechanism responsible for inhibition of IL-12 production by HCV core/gC1qR engagement. The studies proposed here will help to elucidate the mechanisms of HCV core-induced immunosuppression. In addition, they will provide a basis for the rational design of novel therapeutic agents to block the action of HCV-induced immunosuppression.